Autism spectrum disorders (ASDs) are common, debilitating disorders affecting social interaction, communication, and repetitive behaviors. Recent genetic findings have identified mutations in synaptic cell adhesion genes and genes encoding their interacting protein partners at central synapses as genetic causes of autism spectrum disorders. We propose to create novel autism model mouse lines. We will produce both a conditional knockout as well as a global, complete knockout of this synaptic autism gene to mimic complete gene deletion, the most common mutation of this gene linked to autism. Our progress to date is substantial in that we have now demonstrated germline transmission of our conditional knockout construct, thereby establishing founders for both conditional and global knockout lines. We now propose to expand these novel autism model mouse lines and perform initial molecular, biochemical, electrophysiologic and behavioral characterization. In particular, we will measure behaviors corresponding to each of the three core symptom domains in autism spectrum disorder in these mouse lines. The result will be a novel genetic model mouse line of autism, behavioral relevance of the model to autism, and initial studies on brain function using electrophysiology to understand effects on cortical synapses. PUBLIC HEALTH RELEVANCE: Our goal is to better understand a genetic cause of human autism and to use animal models of such causes to identify treatments. This 2-year R21 proposal capitalizes on our significant progress toward creating a novel animal model of autism and will allow us to rapidly advance this project in a brief period. The marriage of our understanding of brain pathology with behavioral abnormalities in these mice will lead to testable hypotheses regarding pharmacologic treatment of autism symptoms in the model and ultimately in autistic patients.